title: Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells.
abstract: The restoration of pluripotency circuits by the reactivation of endogenous stemness factors, such as SOX2, may provide a new paradigm in cancer development. The tumoral stem cell reprogramming hypothesis, i.e., the ability of stemness factors to redirect normal and differentiated tumor cells toward a less-differentiated and stem-like state, adds new layers of complexity to cancer biology, because the effects of such reprogramming may remain dormant until engaged later in response to (epi)genetic and/or (micro)environmental events. To test this hypothesis, we utilized an in vitro model of a SOX2-overexpressing cancer stem cell (CSC)-like cellular state that was recently developed in our laboratory by employing Yamanaka's nuclear reprogramming technology in the estrogen receptor α (ERα)-positive MCF-7 breast cancer cell line. Despite the acquisition of distinct molecular features that were compatible with a breast CSC-like cellular state, such as strong aldehyde dehydrogenase activity, as detected by ALDEFLUOR, and overexpression of the SSEA-4 and CD44 breast CSC markers, the tumor growth-initiating ability of SOX2-overexpressing CSC-like MCF-7 cells solely occurred in female nude mice supplemented with estradiol when compared with MCF-7 parental cells. Ser118 phosphorylation of estrogen receptor α (ERα), which is a pivotal integrator of the genomic and nongenomic E 2/ERα signaling pathways, drastically accumulated in nuclear speckles in the interphase nuclei of SOX2-driven CSC-like cell populations. Moreover, SOX2-positive CSC-like cells accumulated significantly higher numbers of actively dividing cells, and the highest levels of phospho-Ser118-ERα occurred when chromosomes lined up on a metaphase plate. The previously unrecognized link between E 2/ERα signaling and SOX2-driven stem cell circuitry may significantly impact our current understanding of breast cancer initiation and progression, i.e., SOX2 can promote non-genomic E 2 signaling that leads to nuclear phospho-Ser118-ERα, which ultimately exacerbates genomic ER signaling in response to E 2. Because E 2 stimulation has been recently shown to enhance breast tumor-initiating cell survival by downregulating miR-140, which targets SOX2, the establishment of a bidirectional cross-talk interaction between the stem cell self-renewal regulator, SOX2, and the local and systemic ability of E 2 to increase breast CSC activity may have profound implications for the development of new CSC-directed strategies for breast cancer prevention and therapy.
authors.affiliation: Metabolism & Cancer Group; Translational Research Laboratory; Catalan Institute of Oncology-Girona (ICO-Girona); Girona, Spain; Molecular Oncology, Girona Biomedical Research Institute (IDIBGI); Girona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Eugeni
authors.initials: E
authors.lastname: López-Bonet
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Luciano
authors.initials: L
authors.lastname: Vellon
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Iglesias
authors.forename: Olatz
authors.initials: O
authors.lastname: Leis
authors.forename: Angel G
authors.initials: AG
authors.lastname: Martín
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010766:Phosphorylation; D011980:Receptors, Progesterone / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D011980:Receptors, Progesterone; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D004958:Estradiol
keywords: SOX2; breast cancer; cancer stem cells; estradiol; estrogen receptor